JP2022125360A - Treatment for diabetes in patients with insufficient glycemic control despite therapy with oral or non-oral antidiabetic drug - Google Patents

Abstract

PROBLEM TO BE SOLVED: To treat and/or prevent metabolic diseases, particularly diabetes, in patients with insufficient glycemic control despite a therapy with an oral and/or a non-oral antidiabetic drug.

SOLUTION: The invention provides the use of certain DPP-4 inhibitors.

SELECTED DRAWING: None

COPYRIGHT: (C)2022,JPO&INPIT

Description

The present invention relates to metabolic diseases, in particular diabetes, in patients with inadequate glycemic control despite treatment with oral and/or parenteral antidiabetic drugs (especially insulin secretagogues such as sulfonylureas or glinide drugs). Type 2 diabetes mellitus) and certain DPP-4 inhibitors (inhibitors) for the treatment and/or prevention of diseases associated therewith, as well as those DPP-4 inhibitors in said treatment and/or prevention regarding the use of Pharmaceutical compositions for treating and/or preventing metabolic diseases (particularly diabetes) in these patients comprising a DPP-4 inhibitor as specified herein, optionally together with one or more other active substances. is also intended.

Type 2 diabetes mellitus is a common chronic and progressive disease that results from a complex pathophysiology with the dual endocrine effects of insulin resistance and impaired insulin secretion. Treatment of type 2 diabetes typically begins with diet and exercise, followed by oral antidiabetic monotherapy, although conventional monotherapy may initially regulate blood glucose in some patients, it is associated with high secondary related to the rate of invalidity. A limitation of monotherapy in maintaining glycemic control is the reduction in blood glucose, which cannot be sustained during long-term treatment with single agents, at least in some patients, and in combination with multiple oral agents. may be resolved for a limited period of time by obtaining Available data support the conclusion that most patients with type 2 diabetes will fail monotherapy and will require treatment with multiple drugs.
However, because type 2 diabetes is a progressive disease, even patients with a good initial response to combination therapy will eventually require dose escalation or further treatment with insulin. This is because blood glucose levels are very difficult to maintain stable over time. Thus, although existing combination therapies have the potential to enhance glycemic control, they are not without limitations, particularly with regard to long-term efficacy. Moreover, many results indicate that the risk for hypoglycemia may be increased with conventional combination therapy and the need for multiple drugs may also reduce patient compliance. In addition, taking multiple antihyperglycemic agents increases the potential for pharmacokinetic interactions with other drugs the patient may be taking.

Thus, for many patients, these existing pharmacotherapies lead to progressive deterioration of glycemic regulation despite treatment, and do not adequately regulate blood glucose, especially over the long term, thus leading to advanced or late-stage type 2 diabetes ( (including diabetics with inadequate glycemic control, diabetics with secondary failure of drugs and/or insulin indications despite conventional oral or parenteral antidiabetic agents) to obtain and maintain metabolic control I can't.
Therefore, although intensive treatment of hyperglycemia may reduce the incidence of chronic damage, many patients with type 2 diabetes are in part lacking long-term efficacy, tolerance and medication adherence to conventional antihyperglycemic therapeutics. Remains inadequately treated due to limitations of inconvenience.
This high incidence of therapeutic failure is associated with a high rate of long-term hyperglycemia-related complications or chronic injury (microvascular and macrovascular complications such as diabetic nephropathy, retinopathy or neuropathy) in patients with type 2 diabetes. disability, or cardiovascular complications).
Oral antidiabetic agents commonly used in treatment (e.g. first or second line and/or monotherapy or (initial or add-on) combination therapy) include metformin, sulfonylureas, thiazolidinediones, glinides and α- Glucosidase inhibitors include, but are not limited to.
GLP-1 or a GLP-1 analogue, as parenteral antidiabetic agents commonly used in treatment (e.g. first or second line and/or monotherapy or (initial or add-on) combination therapy), and Including but not limited to insulin or insulin analogues.

However, the use of these conventional antidiabetic or antihyperglycemic agents can be associated with various adverse effects (side effects). For example, metformin can be associated with lactic acidosis or gastrointestinal side effects. Sulfonylureas, glinides and insulin or insulin analogues can be associated with hypoglycemia and weight gain. Thiazolidinediones can be associated with edema, bone fracture, weight gain and heart failure/cardiac effects. Alpha-glucosidase blockers and GLP-1 or GLP-1 analogues may also be associated with adverse gastrointestinal effects such as dyspepsia, flatus or diarrhea, or nausea or vomiting.
Glinides, as well as sulfonylureas (SU), stimulate insulin secretion from pancreatic beta cells in a non-glucose-dependent manner, making type 2 diabetes unsuitable or refractory to metformin treatment, particularly in nonobese patients. It is commonly and frequently used as first-line or second-line (single or combination) therapy in patients with However, as noted above, some patients do not always respond well to these conventional oral antidiabetic agents, especially on long-term therapy, and exhibit poor or poor glycemic control despite treatment with sulfonylureas. may show deterioration. Patients on long-term sulfonylurea therapy also experience a decline or depletion of pancreatic beta-cell function over time.
Other oral agents (e.g., metformin/thiazolidinedione) or SU combination therapy (additional and initial dual multiple and triple SU combination therapy), particularly the combination of sulfonylureas with metformin and/or thiazolidinediones, depending on disease stage and/or combination with insulin or (eventually) transition to insulin May be indicated (eg, once daily basal insulin, twice daily premixed insulin or multiple daily insulin, depending on disease stage). However, even with combination therapy, some patients may exhibit poor or deteriorating glycemic control, particularly over time, despite combination therapy.

Thus, continued loss of efficacy over time is a major concern with the use of insulin secretagogues, including glinides and sulfonylureas (SU secondary failure). In addition, sulfonylureas increase plasma levels of insulin and hypoglycemia (which, in addition to weight gain, is one of their major adverse effects, particularly in association with kidney damage and/or in geriatric patients). ) may occur. Thus, with SU drugs, on the one hand, increased sulfonylurea doses may often be required for efficacy, and on the other hand, decreased sulfonylurea doses may be required for safety/tolerability. , and thus SU drugs often require an unsatisfactory compromise.
Therefore, those patients with advanced or late stage type 2 diabetes mellitus (conventional oral and/or parenteral antidiabetic drugs such as metformin, sulfonylureas, thiazolidinediones, glinides and/or α-glucosidase inhibitors, and and/or GLP-1 or GLP-1 analogues, and/or insulin or insulin analogues to provide an effective, safe and tolerable anti-diabetic therapeutic agent, including patients with blood glucose regulation inadequate. A demand exists in the industry.
Further, there is a need in the art to provide adequate glycemic control for diabetic patients with secondary failure of oral antidiabetic therapy.
Further, there is a need in the art to provide prevention (including prevention or delay of progression) of secondary failure of oral anti-diabetic therapy.
Further, there is a need in the art to provide prevention or reduction of the risk of adverse effects associated with (conventional) anti-diabetic therapy.
HbA1c levels, a product of non-enzymatic glycosylation of the hemoglobin B chain, are of particular importance in monitoring the treatment of diabetes mellitus. HbA1c in the sense of "glycemic memory" reflects average blood glucose levels over the previous 4-12 weeks, since its production is substantially dependent on blood glucose levels and red blood cell lifespan. Diabetics whose HbA1c levels were well regulated over time with more intensive diabetes treatment (ie <6.5% of total hemoglobin in the sample) are significantly better protected from diabetic microangiopathy. Available treatments for diabetes can give diabetics an average improvement in their HbA1c levels of the order of 1.0-1.5%. This reduction in HbA1C levels is not sufficient in all diabetics to bring them into the desired target range of <7.0%, preferably <6.5%, more preferably <6% HbA1c.

During glycemic control, in addition to improving HbA1c levels, other treatment goals recommended for patients with type 2 diabetes mellitus are fasting plasma glucose (FPG) levels and postprandial plasma glucose (PPG) levels to normal or as close to normal as possible. is an improvement. The recommended desired target range for preprandial (fasting) plasma glucose is 90-130 mg/dL (or 70-130 mg/dL) or <110 mg/dL, and that for 2-hour postprandial plasma glucose is <180 mg /dL or <140 mg/dL.
Within the meaning of the present invention, as patients with inadequate glycemic control despite treatment with oral or parenteral antidiabetic drugs, 7.0-10% (or 7.5-11%, or 7.5%) despite treatment with said drugs ~10%) HbA1C values include, but are not limited to.
Specific examples of diabetic patients with secondary failure of oral antidiabetic therapy within the meaning of the present invention are
- patients in whom metformin therapy is contraindicated, e.g. patients with one or more contraindications to labeled metformin therapy, e.g.
renal disease, renal impairment, or renal failure (e.g., as specified by the locally approved product information for metformin);
dehydration,
unstable or acute congestive heart failure,
Patients with at least one contraindication selected from acute or chronic metabolic acidosis, and hereditary galactose intolerance, and
- patients suffering from one or more intolerable side effects caused by metformin, in particular gastrointestinal side effects associated with metformin, e.g.
nausea,
vomiting,
diarrhea,
Patients who are unsuitable for metformin treatment are represented, including those suffering from at least one gastrointestinal side effect selected from intestinal gas and severe abdominal discomfort.

Specific examples of patients who may be amenable to the treatment of the present invention are diabetic patients for whom conventional metformin treatment is not appropriate, e.g. Diabetic patients (eg, including geriatric patients aged 60-65 years and older) requiring reduced dose metformin treatment due to depleted/diminished renal function.
Furthermore, because of the increased susceptibility to adverse effects, treatment of elderly patients (60-70 years and older) should often be accompanied by careful monitoring of renal function. Metformin is not usually recommended, especially for geriatric individuals over the age of 80, unless creatinine clearance measurements show that renal function is not compromised. Thus, patients unsuitable for metformin treatment may also include, but are not limited to, geriatric patients aged 60-65 and older, and especially aged 80 and older.
Further specific examples of diabetic patients with secondary failure of oral antidiabetic therapy within the meaning of the present invention are renal disease, renal failure, or e.g. elevated serum creatinine levels (e.g. higher than the upper limit of normal for their age). Serum creatinine levels above 130 - 150 µmol/l or ≥1.5 mg/dl (≥136 µmol/l) in men and ≥1.4 mg/dl (≥124 µmol/l) in women ) or inadequate or impaired renal function (including mild, moderate and severe renal impairment, as indicated by abnormal creatinine clearance (e.g. glomerular filtration rate (GFR) ≤30-60 ml/min)). ).

In this context, and as a more detailed example, mild renal impairment, e.g. 30-50 ml/min creatinine clearance (greater than 1.7 mg/dL to ≤3.0 mg/dL in men and 1.5 mg/dL in women and 1.5 mg/dL in women). dL to less than 2.5 mg/dL), and severe renal impairment may be suggested by, for example, a creatinine clearance of less than 30 ml/min (more than 3.0 mg/dL in men). large, also corresponding to a serum creatine level of greater than 2.5 mg/dL in women). Patients with end-stage renal disease require dialysis.
The enzyme DPP-4 (dipeptidyl peptidase IV) (also known as CD26) is known to effect the cleavage of dipeptides from the N-termini of some proteins with proline or alanine residues at their N-termini. It is a serine protease that Because of this property, DPP-4 inhibitors interfere with plasma levels of bioactive peptides, including the peptide GLP-1, and are considered promising drugs for the treatment of diabetes mellitus.
For example DPP-4 inhibitors and their use, in particular their use in metabolic (diabetic) diseases, are described in WO 2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820 , WO 2004/046148, Wo 2005/051950, Wo 2005/082906, WO 2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769 or WO2007/014886; or Wo 2004/050658, WO 2004/11051 , WO 2005/058901 or WO 2005/097798; or WO 2006/068163, WO 2007/071738 or WO 2008/017670; or WO 2007/128721 or WO 2007/128761.
Additional DPP-4 inhibitors include the following compounds:
- sitagliptin (MK-0431) having the following structural formula A is (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H-[1,2 ,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (also (2R)-4-oxo-4-[3 -(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl) called butan-2-amine).

In one embodiment, sitagliptin is in the form of its dihydrogen phosphate salt, ie, sitagliptin phosphate. In a further embodiment, sitagliptin phosphate is in the form of a crystalline anhydrate or monohydrate. A class of this embodiment represents sitagliptin phosphate monohydrate. Sitagliptin free base and its pharmaceutically acceptable salts are disclosed in US Pat. No. 6,699,871 and Example 7 of WO 03/004498. Crystalline sitagliptin phosphate monohydrate is disclosed in WO 2005/003135 and WO 2007/050485.
Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or its salts.
A tablet formulation of sitagliptin is commercially available under the trade name Januvia®. A tablet formulation of sitagliptin/metformin combination is marketed under the trade name Janumet®.
- vildagliptin (LAF-237) having the following structural formula B is (2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile (also (S)-1-[ (3-Hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine).

Vildagliptin is disclosed in detail in US Pat. No. 6,166,063 and Example 1 of WO 00/34241. A particular salt of vildagliptin is disclosed in WO 2007/019255. A crystalline form of vildagliptin as well as a vildagliptin tablet formulation are disclosed in WO 2006/078593. Vildagliptin may be formulated as described in WO 00/34241 or WO 2005/067976. An improved release vildagliptin formulation is described in WO 2006/135723.
Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or its salts.
A tablet formulation of vildagliptin is expected to be marketed under the trade name Galvus®. A tablet formulation of the vildagliptin/metformin combination is marketed under the trade name Eucreas®.
- saxagliptin (BMS-477118) having the following structural formula C is (1S,3S,5S)-2-{(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl}-2 -azabicyclo[3.1.0]hexane-3-carbonitrile (also called (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoproline nitrile).

Saxagliptin is disclosed in detail in US Pat. No. 6,395,767 and Example 60 of WO 01/68603.
In one embodiment, saxagliptin is in the form of its HCl salt or its mono-benzoate salt as disclosed in WO 2004/052850. In a further embodiment, saxagliptin is in the free base form. In yet another embodiment, saxagliptin is in the form of the free base monohydrate as disclosed in WO 2004/052850. Crystalline forms of HCl salt and free base of saxagliptin are disclosed in WO 2008/131149. Methods for preparing saxagliptin are also disclosed in WO 2005/106011 and WO 2005/115982. Saxagliptin may be formulated in tablets as described in WO 2005/117841.
Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or salt thereof.
- alogliptin (SYR-322) having the following structural formula E is 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4- dihydro-2H-pyrimidin-1-yl}methyl)benzonitrile.

Alogliptin is disclosed in detail in US 2005/261271, EP 1586571 and WO 2005/095381. In one embodiment, alogliptin is in the form of its benzoate, its hydrochloride or its tosylate as disclosed in WO 2007/035629, respectively. A class of this embodiment represents alogliptin benzoate. Polymorphs of alogliptin benzoate are disclosed in WO 2007/035372. Methods for the preparation of alogliptin are disclosed in WO 2007/112368 and more specifically in WO 2007/035629. Alogliptin (ie its benzoate salt) can be formulated and administered in tablets as described in WO 2007/033266. Formulations of alogliptin and metformin or pioglitazone are described in WO 2008/093882 or WO 2009/011451 respectively.
Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or salt thereof.
-(2S)-1-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof, preferably mesylate, or (2S)-1-{[1,1,-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile, or a pharmaceutically acceptable salt thereof.
These compounds and methods for their preparation are described in WO 03/037327. The mesylate salt of the former compound as well as its crystalline polymorph are disclosed in WO 2006/100181. The fumarate salt of the latter compound as well as its crystalline polymorphs are disclosed in WO 2007/071576.
These compounds may be formulated in pharmaceutical compositions as described in WO 2007/017423.
Reference is thus made to these documents, for example, for details on how to make, formulate or use these compounds or salts thereof.
-(S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] Isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one or a pharmaceutically acceptable salt thereof:

This compound and its method of preparation are disclosed in WO 2005/000848. Methods for the preparation of this compound (particularly its dihydrochloride salt) are also disclosed in WO 2008/031749, WO 2008/031750 and WO 2008/055814. This compound may be formulated in a pharmaceutical composition as described in WO 2007/017423.
Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or its salts.
-(3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone (also gosogliptin and or a pharmaceutically acceptable salt thereof:
This compound and methods for its preparation are disclosed in WO 2005/116014 and US 7291618.
Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or its salts.
-(1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl) -5,5-difluoropiperidin-2-one or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation are disclosed in WO 2007/148185 and US 20070299076. Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or its salts.
-(2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2- Carbonitrile (also called melogliptin) or its pharmaceutically acceptable salts

This compound and methods for its preparation are disclosed in WO 2006/040625 and WO 2008/001195. Specifically, the claimed salts include methanesulfonate and toluenesulfonate. Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or its salts.
-(R)-2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro - benzonitrile or a pharmaceutically acceptable salt thereof:

This compound and its method of preparation are disclosed in WO 2005/095381, US 2007060530, WO 2007/033350, WO 2007/035629, WO 2007/074884, WO 2007/112368, WO 2008/114807, WO 2008/114800 and WO 2008/0. disclosed. Specifically, the claimed salts include succinate (WO 2008/067465), benzoate, benzenesulfonate, p-toluenesulfonate, (R)-mandelate and hydrochloride. Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or its salts.
-5-{(S)-2-[2-((S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl )-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide or a pharmaceutically acceptable salt thereof:

This compound and methods for its preparation are disclosed in WO 2006/116157 and US 2006/270701. Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or salt thereof.
-3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine (also teneligliptin and or a pharmaceutically acceptable salt thereof:
This compound and methods for its preparation are disclosed in WO 02/14271. Particular salts are disclosed in WO 2006/088129 and WO 2006/118127 (including hydrochloride, hydrobromide among others). Combination therapy using this compound is described in WO 2006/129785. Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or salt thereof.

- [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid (also called jutogliptin) or a pharmaceutically acceptable salt thereof:
This compound and methods for its preparation are disclosed in WO 2005/047297, WO 2008/109681 and WO 2009/009751. Particular salts are disclosed in WO 2008/027273 (including citrate, tartrate). A formulation of this compound is described in WO 2008/144730. Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or its salts.
-(2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile or its pharmaceutically acceptable salt:
This compound and methods for its preparation are disclosed in WO 2005/075421, US 2008/146818 and WO 2008/114857. Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or its salts.
-2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H- pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile or a pharmaceutically acceptable salt thereof, or 6-[(3R)-3-amino-piperidin-1-yl]-5 -(2-Chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione or a pharmaceutically acceptable salt thereof:
These compounds and methods for their preparation are disclosed in WO 2009/084497 and WO 2006/068163 respectively. Reference is thus made to these documents, for example, for details on how to make, formulate or use this compound or its salts.
For the avoidance of doubt, the disclosure of each of the above-cited documents is expressly incorporated herein by reference.

Within the scope of the present invention, the DPP-4 inhibitors identified herein are useful in patients with advanced or late stage type 2 diabetes (patients with inadequate glycemic control despite oral and/or parenteral antidiabetic agents and / or patients with indications for insulin) to treat and/or prevent (prevent progression or delay It has now been surprisingly found to have unexpected properties, particularly advantageous properties, which make them particularly suitable for treating or delaying onset.
Thus, the present invention also includes treatment (including single drug, double or triple drug) with one or more conventional oral antidiabetic agents selected from metformin, sulfonylureas, thiazolidinediones, glinides and α-glucosidase inhibitors. Provided are DPP-4 inhibitors identified herein for use in treating patients with poor glycemic control regardless.

HbA1c and glucose values are shown after 54 days of treatment of 5-week-old female db/db mice with the indicated compounds (left bar: vehicle; middle bar: BI 1356; right bar: glibenclamide). HbA1c and glucose values are shown after 54 days of treatment of 5-week-old female db/db mice with the indicated compounds (left bar: vehicle; middle bar: BI 1356; right bar: glibenclamide). Shown is the increase in insulin during the OGTT test (oral glucose tolerance test) (left bar: vehicle; middle bar: BI 1356; right bar: glibenclamide).

In another embodiment, the present invention provides one, two or three selected from metformin, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues. Despite treatment with the usual oral or parenteral antidiabetic agents of the species (including single-drug, double- or triple-drug), also monotherapy with e.g. metformin, sulfonylureas, pioglitazone or (basal) insulin. or despite dual combination therapy with metformin/pioglitazone, metformin/sulfonylurea, metformin/(basal) insulin, sulfonylurea/pioglitazone, sulfonylurea/(basal) insulin or pioglitazone/(basal) insulin combination, DPP-4 inhibitors identified herein are provided for use in treating patients with poor glycemic control.
Furthermore, the present invention provides evidence of poor glycemic control despite monotherapy with a sulfonylurea, or dual combination therapy with a metformin/sulfonylurea, sulfonylurea/pioglitazone or sulfonylurea/(basal) insulin combination. A DPP-4 inhibitor identified herein for use in treating a patient is provided.
In particular, the present invention provides DPP-4 inhibitors identified herein for use in treating patients with inadequate glycemic control despite treatment with sulfonylureas.
Further, the present invention provides the DPP identified herein for use in the treatment and/or prevention of metabolic disorders, particularly type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with a sulfonylurea drug. -4 provides inhibitors.
Further, the present invention provides DPP-4 inhibitors as identified herein for use in the treatment and/or prevention of diabetes with sulfonylurea secondary failure.
Furthermore, the present invention relates to the manufacture of pharmaceutical compositions for the treatment and/or prevention of metabolic diseases, in particular type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with sulfonylurea drugs. The use of DPP-4 inhibitors identified in the literature is provided.

Further, the present invention provides a pharmaceutical composition for use in the treatment and/or prevention of metabolic disorders, particularly type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with a sulfonylurea drug, said Pharmaceutical compositions comprise a DPP-4 inhibitor identified herein and optionally one or more pharmaceutically acceptable carriers and/or diluents.
Furthermore, the present invention provides a fixed or non-fixed kit of parts for use in the treatment and/or prevention of metabolic disorders, particularly type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with sulfonylureas. A fixed combination is provided, said combination comprising a DPP-4 inhibitor identified herein and optionally one or more other active agents, such as any of those listed herein.
Furthermore, the present invention provides a pharmaceutical composition for the manufacture of a pharmaceutical composition for the treatment and/or prevention of metabolic diseases, particularly type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with sulfonylurea drugs. Provided is the use of the DPP-4 inhibitors identified herein in combination with any of the above other active agents, eg, those listed herein.
Further, the present invention provides a pharmaceutical composition for use in the treatment and/or prevention of metabolic disorders, particularly type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with a sulfonylurea drug, said A pharmaceutical composition comprises a DPP-4 inhibitor identified herein and optionally one or more other active agents, e.g., any of those listed herein, e.g., separate, sequential for simultaneous, contemporaneous or sequential use.
Further, the present invention provides a method for treating and/or preventing metabolic disease, particularly type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with a sulfonylurea drug, and subject in need thereof ( an effective amount of a DPP-4 inhibitor identified herein, particularly in a human patient, optionally alone or e.g. separately, sequentially, simultaneously, concurrently or over time Administration in combination with one or more other active agents such as any of those listed herein.

In addition, the present invention provides one, two or three normal compounds selected from metformin, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin or insulin analogues. (e.g., metformin, sulfonylurea, pioglitazone or (basal) insulin) despite treatment with antihyperglycemic drugs (e.g., despite treatment with the maximum tolerated oral dose, if applicable) Dual combination therapy despite single therapy or with metformin/pioglitazone, metformin/sulfonylurea, metformin/(basal) insulin, sulfonylurea/pioglitazone, sulfonylurea/(basal) insulin or pioglitazone/(basal) insulin combination metformin, sulfonylureas, thiazolidinediones (e.g. pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, optionally for use in patients with inadequate glycemic control, notwithstanding); and DPP-4 inhibitors identified herein in combination (additionally or initially) with one or two conventional antihyperglycemic agents selected from insulin or insulin analogues.
In a further embodiment of the present invention optionally metformin, sulfonylureas, thiazolidines for use in the (second line) treatment of patients with type 2 diabetes who are poorly controlled on said conventional antihyperglycemic agents alone herein in combination with one conventional antihyperglycemic agent selected from diones (e.g. pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues DPP-4 inhibitors identified in are provided.
In a further embodiment of the present invention, optionally metformin, sulfonyl, for use in the (third-line) treatment of patients with type 2 diabetes who are inadequately controlled with a dual combination of said conventional antihyperglycemic agents. in combination with two conventional antihyperglycemic agents selected from urea, thiazolidinediones (e.g., pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues , DPP-4 inhibitors identified herein are provided.

In a further embodiment of the present invention a drug selected from the group consisting of metformin, pioglitazone, sulfonylureas and insulin for use in treating type 2 diabetic patients with inadequate glycemic control by conventional antihyperglycemic agents alone. DPP-4 inhibitors identified herein are provided in combination with a conventional anti-hyperglycemic agent.
In a further embodiment of the invention, the combination of: metformin and pioglitazone, metformin and a sulfonylurea, for use in the treatment of type 2 diabetic patients with inadequate glycemic control by two conventional antihyperglycemic agents, DPP-4 inhibition as specified herein in combination with two conventional antihyperglycemic agents selected from the group consisting of metformin and insulin, sulfonylurea and pioglitazone, sulfonylurea and insulin, and pioglitazone and insulin agents are provided.
In particular, the present invention is identified herein in combination with a sulfonylurea for use in treating type 2 diabetes patients with inadequate glycemic control despite monotherapy with a sulfonylurea at the maximum tolerated dose. DPP-4 inhibitors are provided.
Further, the present invention has been identified herein in combination with a sulfonylurea and metformin for use in treating type 2 diabetes patients with inadequate glycemic control despite dual combination therapy with a sulfonylurea and metformin. DPP-4 inhibitors are provided.
Further, the present invention has been identified herein in combination with a sulfonylurea and pioglitazone for use in treating type 2 diabetes patients with inadequate glycemic control despite dual combination therapy with a sulfonylurea and pioglitazone. DPP-4 inhibitors are provided.
Further, the present invention is identified herein in combination with a sulfonylurea and insulin for use in treating type 2 diabetic patients with inadequate glycemic control despite dual combination therapy with a sulfonylurea and insulin. DPP-4 inhibitors are provided.
Additionally, the DPP-4 inhibitors identified herein may be used in diabetic patients with inadequate glycemic control (SU secondary ineffectiveness) despite treatment with oral antidiabetic agents, particularly sulfonylureas, as one of the following methods: more than one can be beneficial.
- to prevent, slow the progression of, delay or treat a metabolic disorder,
- for improving blood sugar regulation and/or reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c,
- to prevent, slow, delay or treat a condition or disease selected from the group consisting of complications of diabetes mellitus,
- to reduce weight or prevent weight gain or promote weight loss,
- to prevent or treat pancreatic beta-cell degeneration and/or improve and/or restore pancreatic beta-cell function and/or stimulate and/or restore pancreatic insulin secretion function, and/ or - to maintain and/or improve insulin sensitivity and/or treat or prevent hyperinsulinemia and/or insulin resistance.

Examples of such metabolic diseases or disorders amenable to treatment of the present invention in patients with secondary failure of oral antidiabetic therapy include type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia. , hyperlipidemia, hypercholesterolemia, dyslipidemia, metabolic syndrome X, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction and osteoporosis. include, but are not limited to.
Furthermore, the present invention provides a general class of drugs selected in particular from metformin, sulfonylureas, thiazolidinediones (e.g. pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues. For the manufacture of drugs for one or more of the following purposes in patients with inadequate glycemic control despite single, double or triple therapy with oral or parenteral antidiabetic drugs, if necessary, one Provided is the use of the DPP-4 inhibitors identified herein in combination with any of the above other active agents, eg, those listed herein.
- metabolic disorders or diseases such as type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, excess body weight, Obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), retinopathy, neurology preventing, slowing, delaying or treating disorders, nephropathy and/or metabolic syndrome;
- for improving blood sugar regulation and/or reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c,
- prevent, slow or reverse the progression of impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or metabolic syndrome to type 2 diabetes mellitus,
- complications of diabetes mellitus, such as micro- and macrovascular diseases, such as nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative diseases or Cognitive impairment, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable prevent, reduce the risk of, slow progression of, delay or treat angina pectris, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart failure, vascular restenosis, and/or stroke;
- reduce weight or prevent weight gain or promote weight loss,
- prevent, delay or treat degeneration of pancreatic beta cells and/or decline in pancreatic beta cell function and/or improve and/or restore pancreatic beta cell function and/or pancreatic insulin secretion stimulate and/or restore the function of
- prevent, slow, delay or treat non-alcoholic fatty liver disease (NAFLD), including hepatic steatosis, non-alcoholic hepatic steatosis (NASH) and/or liver fibrosis,
- to prevent, slow, delay or treat type 2 diabetes that is primary or secondary refractory to conventional (oral) hyperglycemic agent single or combination therapy,
- obtaining a reduction in the dose of conventional antihyperglycemic agents required for adequate therapeutic effect,
- reduce the risk of adverse effects associated with conventional antihyperglycemic drugs, and/or - maintain and/or improve insulin sensitivity, and/or treat or prevent hyperinsulinemia and/or insulin resistance. .

A particular embodiment of the present invention relates to DPP-4 inhibitors identified herein for obtaining and/or maintaining glycemic control in type 2 diabetic patients with sulfonylurea secondary failure.
Another particular embodiment of the present invention relates to DPP-4 inhibitors identified herein for use in preventing (including preventing or delaying progression of) diabetes secondary to SU failure.
Another particular embodiment of the present invention is for use in preventing or reducing the risk of adverse effects associated with SU antidiabetic therapy, such as hypoglycemia and/or weight gain (or even gaining weight loss). and for DPP-4 inhibitors identified herein for use in clinical trials.
Another particular embodiment of the present invention relates to a DPP-4 inhibitor as identified herein for use in the treatment of diabetes with secondary sulfonylurea failure, wherein said DPP-4 inhibitor is a sulfonylurea Add-on or initial combination therapy with single or dual drugs (e.g., as adjunctive therapy to SU drugs with or without metformin), or optionally one or more other therapeutic agents, e.g., metformin and /or used as a replacement for sulfonylurea drugs in combination with thiazolidinediones (eg, pioglitazone).
Another specific embodiment of the present invention is a patient with inadequate glycemic control (e.g., 7.5% to 10%) despite treatment with a sulfonylurea drug (e.g., glibenclamide, glipizide, or glimeprid, with or without metformin). improve HbA1c and/or FPG (e.g., mean reduction from baseline), reduce glucose excursion, and/or improve insulin secretion DPP-4 inhibitors for use in patients.

Other aspects of the invention will become apparent from the foregoing and following description.
DPP-4 inhibitors within the meaning of the present invention include, but are not limited to, any of those DPP-4 inhibitors listed above and below, preferably orally active DPP-4 inhibitors.
An embodiment of the present invention relates to a DPP-4 inhibitor for use in the treatment and/or prevention of metabolic disease (e.g., type 2 diabetes mellitus) in type 2 diabetes patients with secondary failure of oral antidiabetic therapy. wherein said patient further suffers from renal disease, renal failure or renal impairment and in particular said DPP-4 inhibitor is administered to said patient at the same dose level as for patients with normal renal function. Thus, for example, the DPP-4 inhibitor does not require downward dosing adjustments for impaired renal function.
Another embodiment of the present invention relates to a DPP-4 inhibitor for use in the treatment and/or prevention of metabolic disease (particularly type 2 diabetes mellitus) in type 2 diabetes patients with secondary failure of oral antidiabetic therapy. and the patient is also refractory or unsuitable for metformin therapy, or has an intolerance or contraindication to metformin, such as any of the intolerance or contraindications specified above or below. require metformin dose reduction.
DPP-4 inhibitors that may be suggested for the purposes of the present invention (particularly for patients with impaired renal function) may be such DPP-4 inhibitors, the active metabolites of which are comparable to It preferably has a broad therapeutic window (eg, greater than 100-fold) and/or is primarily excreted, especially by hepatic metabolism or biliary excretion.
More particularly, DPP-4 inhibitors particularly suitable for the above purposes of the present invention (especially patients with impaired renal function) may be such orally administered DPP-4 inhibitors, which may be compared. have a broad (e.g., >100-fold) therapeutic window and/or satisfy one or more of the following pharmacokinetic properties (preferably at their therapeutic oral dose levels):
- The DPP-4 inhibitor is substantially or primarily excreted via the liver (e.g. >80% or even >90% of the oral dose administered) and/or renal excretion represents a substantial elimination route. no, or represent only a minor route of elimination (e.g. <10%, preferably <7% of the oral dose administered as measured by post-elimination radiolabeled carbon ( ^14C ) substance oral dose);
- DPP-4 inhibitors are excreted largely unchanged as the parent drug (e.g. mean > 70% or > 80% of excreted radioactivity in urine and feces after oral dosing of radiolabeled carbon ( ¹⁴ C) material). , or preferably 90%) and/or eliminated by metabolism to substantially no or only marginal extent (e.g. <30%, or <20%, or preferably 10%);
- One or more (major) metabolites of the DPP-4 inhibitor is pharmacologically inactive. For example, the major metabolite does not bind to the target enzyme DPP-4, and optionally it is eliminated more rapidly than the parent compound (e.g. <20 hours, or preferably < about 16 hours, e.g. 15.9 hours). at the terminal half-life of time).

Additional properties of DPP-4 inhibitors, which may be attractive for the above purposes of the present invention, may be one or more of the following: rapid attainment of steady state (e.g. therapeutic oral steady-state plasma levels (e.g., >90% of steady-state plasma concentration) on days 2-4 of treatment by dose level), little accumulation (e.g., mean accumulation ratio R _{A, at AUC} ≤ 1.4), and/or preserving long lasting effects on DPP-4 inhibition (e.g., near complete (>90% ) DPP-4 suppression, >80% suppression over a 24-hour interval after a single daily intake of a therapeutic oral drug dose), ≥80% (already on the first day of treatment) 2-hour postprandial blood glucose excursion at the therapeutic dose level. A significant decrease in width and cumulative amount of unchanged parent compound excreted in the urine on the first day that is less than 1% of the administered dose and does not increase by more than 3-6% at steady state.
Thus, the present invention also relates to the treatment of metabolic disorders, particularly patients for whom metformin treatment is unsuitable due to intolerance or contraindications to metformin, and more particularly type 2 diabetes mellitus in patients with renal disease, renal insufficiency or renal failure. and/or to a DPP-4 inhibitor for use in prophylaxis, wherein said DPP-4 inhibitor is not excreted by the kidney to a substantial extent or only to a minor extent (e.g. an administered oral dose < 10%, preferably < 7%) of the body is excreted (eg, as measured by radiolabeled carbon ( ¹⁴ C) substance oral dose after elimination).
In addition, the present invention also relates to the treatment of metabolic diseases, particularly patients for whom metformin treatment is unsuitable due to intolerance or contraindications to metformin, more particularly type 2 diabetes mellitus in patients with renal disease, renal insufficiency or renal impairment. and/or a DPP-4 inhibitor for use in prophylaxis, said DPP-4 inhibitor being substantially or primarily excreted by the liver (e.g. radiolabeled carbon ( ¹⁴ C) (measured by substance oral dose).

In addition, the present invention also relates to the treatment of metabolic diseases, particularly patients for whom metformin treatment is unsuitable due to intolerance or contraindications to metformin, more particularly type 2 diabetes mellitus in patients with renal disease, renal insufficiency or renal impairment. and/or DPP-4 inhibitors for use in prophylaxis,
The DPP-4 inhibitor is excreted primarily unchanged as the parent compound (e.g., an average >70% of the radioactivity excreted in urine and feces after oral administration of radiolabeled carbon ( ¹⁴ C) material, or > 80% or preferably 90%),
the DPP-4 inhibitor is not eliminated by metabolism to a substantial extent, or is eliminated to only a minor extent, and/or the major metabolites of the DPP-4 inhibitor are pharmacologically inactive, or It is characterized by having a relatively wide therapeutic window.
In a first embodiment (embodiment A), the DPP-4 inhibitor in the context of this invention is any DPP-4 inhibitor of the formula below or a pharmaceutically acceptable salt thereof.
Formula (I)

もしくは式 (II)

又は式 (III)

或いは式 (IV)

or formula (II)

or formula (III)

or formula (IV)

wherein R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6 -dimethyl-pyrimidin-2-yl)methyl, and R2 is 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino or (2-(S )-amino-propyl)-methylamino.

In a second embodiment (embodiment B) the DPP-4 inhibitor in the context of the present invention is sitagliptin, vildagliptin, saxagliptin, alogliptin,
(2S)-1-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile,
(2S)-1-{[1,1,-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile,
(S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline -3-yl)-4-fluoromethyl-pyrrolidin-2-one,
(3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone,
(1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)- 5,5-difluoropiperidin-2-one,
(2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbo nitrile,
(R)-2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro- benzonitrile,
5-{(S)-2-[2-((S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl) -10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide,
3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,
[(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid,
(2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile,
2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo [3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile, and
6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2- d] A DPP-4 inhibitor selected from the group consisting of pyrimidine-2,4-diones or a pharmaceutically acceptable salt thereof.

With respect to the first embodiment (embodiment A), preferred DPP-4 inhibitors are any or all of the following compounds and pharmaceutically acceptable salts thereof.
・1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl )-xanthine (cf. WO 2004/018468, Example 2 (142)):

・1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidine-1- yl)-xanthine (cf. WO 2004/018468, Example 2 (252)):

・1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine ( WO 2004/018468, Example 2 (80)):

・2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo [4,5-d]pyridazin-4-one (WO 2004/050658, compare Example 136):

・1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methyl-propyl)-methyl Amino]-xanthines (cf. WO 2006/029769, Example 2(1)):

・1-[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl )-xanthine (cf. WO 2005/085246, Example 1(30)):

・1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (WO 2005/ 085246, see Example 1 (39)):

・1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methyl Amino]-xanthines (cf. WO 2006/029769, Example 2(4)):

・1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl )-xanthine (cf. WO 2005/085246, Example 1(52)):

・1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl )-xanthine (cf. WO 2005/085246, Example 1 (81)):

・1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidine-1 -yl)-xanthine (cf. WO 2005/085246, Example 1 (82)):

・1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine ( WO 2005/085246, Example 1 (83)):

These DPP-4 inhibitors are distinct from structurally comparable DPP-4 inhibitors. because they combine long-lasting action, receptor selectivity and favorable side-effect profiles with exceptional potency and favorable pharmacological properties, or unexpected when combined with other pharmaceutically active substances. because it provides a therapeutic benefit or improvement. Their preparation is disclosed in the publications mentioned.
A more preferred DPP-4 inhibitor among the above DPP-4 inhibitors of embodiment A of this invention is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2- Butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, especially its free base (also known as BI 1356).
Unless otherwise stated, according to the invention the definitions of the active compounds (including DPP-4 inhibitors) mentioned above and below are not only their pharmaceutically acceptable salts, but also their hydrates. , solvates and polymorphs. Particular reference is made to what is said herein with regard to salts, hydrates and polymorphs thereof.
With respect to embodiment A, methods of synthesizing the DPP-4 inhibitors of embodiment A of this invention are known to those skilled in the art. Advantageously, the DPP-4 inhibitors of embodiment A of the present invention may be prepared using synthetic methods described in the literature. Thus, for example, purine derivatives of formula (I) are obtained as described in WO 2002/068420, WO 2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, the disclosure of which is hereby incorporated by reference. Included in the description. Purine derivatives of formula (II) are obtained, for example, as described in WO 2004/050658 or WO 2005/110999, the disclosures of which are incorporated herein.
Purine derivatives of formulas (III) and (IV) are obtained, for example, as described in WO 2006/068163, WO 2007/071738 or WO 2008/017670, the disclosures of which are incorporated herein. The preparation of these DPP-4 inhibitors, detailed above, is disclosed in the publications cited in connection therewith. Polymorphic crystal variations and formulations of particular DPP-4 inhibitors are disclosed in WO 2007/128721 and WO 2007/128724, respectively, the disclosures of which are incorporated herein in their entirety. Formulations of specific DPP-4 inhibitors with metformin or other combination partners are described in PCT/EP2009053978, the disclosure of which is hereby incorporated in its entirety. Typical doses for the BI 1356/metformin dual combination are 2.5/500 mg, 2.5/850 mg and 2.5/1000 mg.
With respect to embodiment B, methods for synthesizing DPP-4 inhibitors of embodiment B are described in the scientific literature and/or published patent documents, particularly those cited herein.

For pharmaceutical applications in warm-blooded vertebrates, especially humans, the compounds of the invention are normally used in doses of 0.001-100 mg/kg body weight, preferably 0.1-15 mg/kg body weight, in each case 1 to 4 times daily. be done. For this purpose, the compounds are combined with one or more inert conventional carriers and/or diluents, such as maize starch, lactose, glucose, microcrystalline cellulose, stearic acid, optionally combined with other active substances. Magnesium, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fats or suitable thereof can be incorporated into conventional galenic formulations, such as simple or coated tablets, capsules, powders, suspensions or suppositories, together with other mixtures.
The pharmaceutical compositions of the invention containing the DPP-4 inhibitors identified herein are thus prepared by those skilled in the art using pharmaceutically acceptable formulation excipients as described in the art. Examples of such excipients include diluents, binders, carriers, fillers, lubricants, glidants, crystallization retardants, disintegrants, solubilizers, colorants, pH modifiers, surfactants and emulsifiers. include, but are not limited to.
Examples of suitable diluents for compounds of embodiment A include cellulose powder, calcium hydrogen phosphate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol. Among these diluents, mannitol, low-substituted hydroxypropylcellulose and pregelatinized starch should be emphasized.
Examples of suitable lubricants for compounds of embodiment A include talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate. Among these lubricants, magnesium stearate should be emphasized.

Examples of suitable binders for compounds of embodiment A include copovidone (a copolymer of vinylpyrrolidone and other vinyl derivatives), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (povidone), pregelatin. modified starch, or low-substituted hydroxypropyl cellulose (L-HPC). Among these binders, copovidone and pregelatinized starch should be emphasized.
Examples of suitable disintegrants for compounds of embodiment A include corn starch or crospovidone. Among these disintegrants, corn starch should be emphasized.
Suitable methods for preparing a pharmaceutical formulation of a DPP-4 inhibitor according to embodiment A of the invention are Direct tableting of the active agent in a powder mixture with suitable tableting excipients;
- granulation with suitable excipients followed by mixing with suitable excipients and subsequent tableting as well as film coating; or - filling of powder mixtures or granules into capsules.
Suitable granulation methods are: Wet granulation in an intensive mixer followed by fluid bed drying;
- One-pot granulation;
• fluid bed granulation; or • dry granulation (eg by roll compaction) with suitable excipients and subsequent tablet formation or filling into capsules.

An exemplary composition of a DPP-4 inhibitor according to embodiment A of the present invention is: first diluent mannitol, pregelatinized starch as second diluent with additional binder properties, binder copovidone, disintegrant Corn starch and magnesium stearate as lubricants, optionally copovidone and/or corn starch.
For details on dosage forms, formulations and administration of DPP-4 inhibitors of the present invention, reference is made to the scientific literature and/or published patent documents, particularly those cited herein.
With respect to the first embodiment (embodiment A), typically required doses of the DPP-4 inhibitors listed herein in embodiment A are 0.1 mg to 10 mg when administered intravenously. , preferably 0.25 mg to 5 mg, and when administered orally, 0.5 mg to 100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg to 10 mg or 1 mg to 5 mg , administered 1 to 4 times daily in each case. Thus, for example, 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidine- The dose of 1-yl)-xanthine when administered orally is 0.5 mg to 10 mg per patient per day, preferably 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day.
Dosage forms prepared with a pharmaceutical composition comprising a DPP-4 inhibitor listed herein in embodiment A contain the active ingredient in a dosage range of 0.1-100 mg. Thus, for example, 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidine- Specific doses of 1-yl)-xanthine are 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.

With respect to the second embodiment (embodiment B), the dose of the DPP-4 inhibitors recited herein in embodiment B to be administered to a mammal, e.g., a human weighing about 70 kg, is generally from about 0.5 mg to about 350 mg, such as from about 10 mg to about 250 mg, preferably 20-200 mg, more preferably 20-100 mg, or preferably 1-4 single doses of the active moiety, such as , which may be of the same size), from about 0.5 mg to about 20 mg, preferably 2.5-10 mg per person per day. Single doses include, for example, 10, 25, 40, 50, 75, 100, 150 and 200 mg of DPP-4 inhibitor active moiety.
The dose of the DPP-4 inhibitor sitagliptin is usually 25-200 mg of active moiety. The recommended dose of sitagliptin is 100 mg calculated for the active moiety (free base anhydrate) once daily. Unit doses of sitagliptin free base anhydrate (active moiety) are 25, 50, 75, 100, 150 and 200 mg. Particular unit doses (eg per tablet) of sitagliptin are 25, 50 and 100 mg. Equivalent amounts of sitagliptin phosphate monohydrate to sitagliptin free base anhydrate are used in the pharmaceutical composition, namely 32.13, 64.25, 96.38, 128.5, 192.75 and 257 mg respectively. Adjusted doses of sitagliptin 25 and 50 mg are used in patients with renal failure. Typical dosages for sitagliptin/metformin double combinations are 50/500 mg and 50/1000 mg.
The dosage range of the DPP-4 inhibitor vildagliptin is usually 10-150 mg daily, especially 25-150 mg, 25-100 mg or 25-50 mg or 50-100 mg daily. Particular examples of daily oral doses are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg. In a more particular aspect, the daily dose of vildagliptin may be 25-150 mg or 50-100 mg. In another more specific aspect, the daily dose of vildagliptin may be 50 or 100 mg. Application of the active ingredient may occur up to three times a day, preferably once or twice a day. Specific doses are vildagliptin 50 mg or 100 mg. Typical doses for the dual vildagliptin/metformin combination are 50/850 mg and 50/1000 mg.

Alogliptin is administered at daily doses of 5 mg to 250 mg/day of alogliptin, optionally 10 mg to 200 mg, optionally 10 mg to 150 mg, and optionally 10 mg to 100 mg (molecular weight of the free base form of alogliptin in each case). ) may be administered to the patient. Thus, specific dosages that may be used include, but are not limited to, 10 mg, 12.5 mg, 20 mg, 25 mg, 50 mg, 75 mg and 100 mg of alogliptin per day. Alogliptin may be administered in its free base form or as a pharmaceutically acceptable salt.
Saxagliptin may be administered to the patient in daily doses of 2.5 mg/day to 100 mg/day, optionally 2.5 mg to 50 mg. Particular dosages that may be used include, but are not limited to, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg and 100 mg of saxagliptin per day. Typical doses for dual saxagliptin/metformin combinations are 2.5/500 mg and 2.5/1000 mg.
A particular embodiment of the DPP-4 inhibitors of the present invention are low dosage levels, for example dosage levels <100 mg or <70 mg per patient per day, preferably <50 mg per patient per day, more preferably <30 mg or < 20 mg, even more preferably from 1 mg to 10 mg (if required divided into 1 to 4 single doses, especially 1 or 2 single doses, which are of the same size). may be used), especially those orally administered DPP-4 inhibitors which are therapeutically effective from 1 mg to 5 mg (more particularly 5 mg), preferably orally administered once daily. , more preferably at any time of the day with or without food. Thus, for example, a daily oral dose of 5 mg BI 1356 is a once daily dosing regimen (i.e. 5 mg BI 1356 once daily) or a twice daily dosing regimen (i.e. 2.5 mg BI 1356) may be administered with or without food at any time of the day.

A particularly preferred DPP-4 inhibitor to be emphasized within the meaning of the present invention is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)- 8-(3-(R)-Amino-piperidin-1-yl)-xanthine (also known as BI 1356). BI 1356 exhibits high potency, a 24 hour duration of action, and a wide therapeutic window. In patients with type 2 diabetes who received multiple oral doses of 1, 2.5, 5 or 10 mg BI 1356 once daily for 12 days, BI 1356 exhibited favorable pharmacodynamic and pharmacokinetic profiles (see table below). 1) with rapid attainment of steady state (e.g., steady state plasma levels (>90% of premedication plasma concentration on day 13) on days 2-5 of treatment in all dose groups). ), little accumulation (e.g. mean accumulation ratio R _A,AUC ≤ 1.4 at doses above 1 mg) and long-lasting effects on DPP-4 inhibition (e.g. 5 mg and 10 mg dose levels). near complete (>90%) DPP-4 inhibition at steady state (92.3 and 97.3% inhibition, respectively, and >80% inhibition at 24-hour intervals after drug ingestion) as well as at doses ≥2.5 mg showed a significant reduction in the 2-hour postprandial blood glucose excursion of ≧80% (already on day 1), indicating that the cumulative amount of unchanged parent compound excreted in the urine on day 1 was greater than the dose administered. less than 1%, rising to ≤3-6% on day 12 (renal clearance CL _R,ss from about 14 to about 70 mL/min for the administered oral dose, e.g., 5 mg per dose, renal clearance is approximately 70 ml/min). In humans with type 2 diabetes, BI 1356 exhibits placebo-like safety and tolerability. At low doses of about >5 mg, BI 1356 acts as a true once-daily oral drug with a full 24-hour period of DPP-4 inhibition. At therapeutic oral dose levels, BI 1356 is excreted primarily by the liver and only to a minor extent (<7% of the administered oral dose) by the kidney. BI 1356 is excreted unchanged primarily via the bile. The proportion of BI 1356 cleared by the kidneys increased only very slightly over time with increasing dose, so that it would probably not be necessary to alter the dose of BI 1356 based on the patient's renal function. Non-renal elimination of BI 1356, combined with its low accumulation potential and wide margin of safety, may be of considerable benefit in patient populations with high prevalence of renal failure and diabetic nephropathy.
Table 1: Geometric Mean (gMean) and Geometric Percent Change (gCV) of BI 1356 Pharmacokinetic Parameters at Steady State (Day 12)

Since different metabolic dysfunctions often occur simultaneously, it is quite often indicated to combine several different active ingredients with each other. Thus, depending on the diagnosed dysfunction, DPP-4 inhibitors may be added to active substances customary for the respective disorder, such as other anti-diabetic substances, in particular lowering blood sugar levels or blood lipid levels, Improved therapeutic results may be obtained when combined with one or more active agents selected from among active agents that increase HDL levels, lower blood pressure, or are indicated for the treatment of atherosclerosis or obesity. unknown.
Besides their use in monotherapy, the DPP-4 inhibitors described above may also be used in conjunction with other active agents to give improved therapeutic results. Such combination therapy may be given as a free combination of substances or in the form of fixed combinations, eg in tablets or capsules. Pharmaceutical formulations of the combination partners required for this may be obtained commercially as pharmaceutical compositions or may be formulated by those skilled in the art using routine methods. Active substances which may be obtained commercially as pharmaceutical compositions are found in the prior art in many places, e.g. the list of drugs appearing annually, the "Rote Liste" of the Federal Association of the Pharmaceutical Industry, or the "Physicians'Desk". It is described in an annually updated compilation of manufacturer's information on prescription drugs known as the Reference.

Examples of anti-diabetic combination partners are metformin; sulfonylureas such as glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornuride and gliclazide; nateglinide; repaglinide; thiazolidinediones such as rosiglitazone and pioglitazone; PPAR-gamma agonists such as GI 262570; PPAR-gamma antagonists; PPAR-gamma/alpha modulators such as tesaglitazar, moraglitazar, alleglitazar, indeglitazar and KRP297; PPAR-gamma/alpha/delta modulators; betas such as AICAR; acetyl-CoA carboxylase (ACC1 and ACC2) inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors; pancreatic beta cell GCRP agonists such as SMT3-receptor-agonists and GPR119; inhibitors; FGF19 agonists or analogues; alpha-glucosidase blockers such as acarbose, voglibose and miglitol; alpha2-antagonists; insulin and insulin analogues such as human insulin, insulin lispro, insulin glucose, r-DNA-insulin aspart, NPH insulin, insulin detemir, insulin zinc suspension and insulin glargine; gastric acid-inhibiting peptide (GIP); pramlintide, davalintide; amylin and amylin analogues or GLP-1 and GLP-1 analogues such as exendin-4 , e.g. exenatide, exenatide LAR, liraglutide, taspoglutide, AVE-0010, LY-2428757, LY-2189265, semaglutide or arbiglutide; -inhibitors of phosphatases; fructose-1,6-bisphosphatase modulators; glycogen phosphorylase modulators; glucagon receptor antagonists; phosphoenolpyruvate carboxynase (PEPCK) inhibitors; inhibitor of (50 mg to 600 mg), e.g. PDGF-receptor-kinase (see EP-A-564409, WO 98/35958, US 5093330, WO 2004/005281, and WO 2006/041976); protein mochelators (including glucokinase activators); glycogen synthase kinase inhibitors; inhibitors of SH2-domain containing inositol 5-phosphatase type 2 (SHIP2); IKK inhibitors, such as high-dose salicylates; JNK1 inhibitors; kinase C-theta inhibitors; beta3 agonists such as ritobegron, YM 178, solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825; aldose reductase inhibitors such as AS 3201, zenarestat, fidarestat, epalrestat, ranirestat, NZ-314, CP-744809 and CT-112; SGLT-1 or SGLT-2 inhibitors such as dapagliflozin, sergliflozin, atigliflozin, larnagliflozin or canagliflozin (or from WO 2009/035969 GPR40 modulators; SCD-1 inhibitors; CCR-2 antagonists; dopamine receptor agonists (bromocriptine mesylate [Cycloset]); It is a DPP IV inhibitor.

Metformin is about 100 mg to 500 mg, or 200 mg to 850 mg (1-3 times daily), or about 300 mg to 1000 mg, once or twice daily, or about 100 mg to 1000 mg, or preferably 500 mg once or twice daily. Delayed release metformin is usually given in doses varying from about 500 mg to 2000 mg to 2500 mg per day using various dosing regimens in doses of ˜1000 mg or about 500 mg to 2000 mg once daily. Particular doses may be metformin hydrochloride 250, 500, 625, 750, 850 and 1000 mg.
The dose of pioglitazone is usually about 1-10 mg, 15 mg, 30 mg, or 45 mg once daily.
Rosiglitazone is usually given in doses of 4-8 mg once (or twice divided) daily (typical doses are 2, 4 and 8 mg).
Glibenclamide (glyburide) is usually given in doses of 2.5-5 mg to 20 mg once daily (or divided into two doses) (typical doses are 1.25, 2.5 and 5 mg) or pulverized Glibenclamide is given in doses of 0.75-3 mg to 12 mg once (or divided into two doses) daily (typical doses are 1.5, 3, 4.5 and 6 mg).
Glipizide is usually given in doses of 2.5 mg to 10-20 mg once daily (up to 40 mg in two divided doses) (typical doses are 5 mg and 10 mg), or extended-release glipizide It is given in doses of 5 mg to 10 mg (up to 20 mg) once daily (typical doses are 2.5, 5 and 10 mg).
Glimepiride is usually given in doses from 1-2 mg to 4 mg (up to 8 mg) once daily (typical doses are 1, 2 and 4 mg).
Dual combinations of glibenclamide/metformin are usually given in doses from 1.25/250 mg once daily to 10/1000 mg twice daily (typical doses are 1.25/250, 2.5/500 and 5/500 mg). ).
Glipizide/metformin dual combinations are usually given in doses from 2.5/250 mg to 10/1000 mg twice daily (typical doses are 2.5/250, 2.5/500 and 5/500 mg).
Glimepiride/metformin dual combinations are usually given in doses from 1/250 mg to 4/1000 mg twice daily.
Rosiglitazone/glimepiride dual combination is usually given in doses from 4/1 mg once or twice daily to 4/2 mg twice daily (typical doses are 4/1, 4/2, 4/2 4, 8/2 and 8/4 mg).
The pioglutazone/glimepiride dual combination is usually given in doses of 30/2 mg to 30/4 mg once daily (typical doses are 30/4 and 45/4 mg).
Rosiglitazone/metformin dual combination is usually given in doses from 1/500 mg to 4/1000 mg twice daily (typical doses are 1/500, 2/500, 4/500, 2/1000 and 2/1000). 4/1000 mg).
The double combination of pioglitazone/metformin is usually given in doses from 15/500 mg once or twice daily to 15/850 mg three times daily (typical doses are 15/500 and 15/850 mg). .

The nonsulfonylurea insulin secretagogue nateglinide is usually given with meals in doses of 60 mg to 120 mg (up to 360 mg/day, typical doses are 60 and 120 mg), and repaglinide is given with meals at It is usually given in doses up to mg (up to 16 mg/day, typical doses are 0.5, 1 and 2 mg). Repaglinide/metformin dual combinations are available in doses of 1/500 and 2/850 mg.
Acarbose is usually given with meals in doses of 25 mg to 100 mg (up to 300 mg/day, typical doses are 25, 50 and 100 mg). Miglitol is usually given with meals in doses from 25 mg to 100 mg (up to 300 mg/day, typical doses are 25, 50 and 100 mg).
Conventional antidiabetic and antihyperglycemic agents typically used in monotherapy or double or triple (add-on or initial) combination therapy include metformin, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP -1 and GLP-1 analogues, as well as insulin and insulin analogues, including, but not limited to, those agents exemplified herein, including combinations thereof.

Examples of combination partners that lower blood lipid levels are HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin; fibrates such as bezafibrate, fenofibrate, clofib nicotinic acid and its derivatives such as acipimox; PPAR-alpha agonists; PPAR-delta agonists; inhibitors of acyl-coenzyme A; cholesterol acyltransferase (ACAT; EC 2.3.1.26), e.g. avasimibe; cholesterol absorption inhibitors, e.g. ezetimibe; substances that bind bile acids, e.g. cholestyramine, colestipol and colesevelam; inhibitors of bile acid transport; , reverse D4F, LXR modulating activity and FXR modulating activity; CETP inhibitors such as torcetrapib, JTT-705 (dalcetrapib) or compound 12 (anacetrapib) from WO 2007/005572; LDL receptor modulators; and ApoB100 antisense. is RNA.
The dosage of atorvastatin is usually 1 mg to 40 mg, or 10 mg to 80 mg once daily.
Examples of combination partners that lower blood pressure are beta-blockers such as atenolol, bisoprol, celiprolol, metoprolol and carvedilol; diuretics such as hydrochlorothiazide, chlorthalidone, xipamide, furosemide, piretanide, torasemide, spironolactone, eplerenone, amiloride and triamterene; calcium channel blockers such as amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, lercanipidine, manidipine, isradipine, nilvadipine, verapamil, gallopamil and diltiazem; ACE inhibitors such as ramipril, lisinopril, cilazapril, quinapril, Angiotensin II receptor blockers (ARBs) such as telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan and eprosartan, as well as captopril, enalapril, benazepril, perindopril, fosinopril and trandolapril.
The dose of telmisartan is usually 20 mg to 320 mg, or 40 mg to 160 mg per day.

Examples of combination partners that increase HDL levels in the blood are cholesteryl ester transfer protein (CETP) inhibitors; inhibitors of endothelial lipase; regulators of ABC1; LXR alpha antagonists; LXR beta agonists; PPAR-delta agonists; Regulators and substances that increase the expression and/or plasma concentration of apolipoprotein AI.
Examples of combination partners for the treatment of obesity are Sibutramine; Tetrahydrolipstatin (orlistat); Alizyme; Dexfenfluramine; Axocaine; NPY2 antagonists as well as NPY5 antagonists; beta3-AR agonists such as SB-418790 and AD-9677; 5HT2c receptor agonists such as APD 356 (lorcaserin); myostatin inhibitors; Acrp30 and adiponectin; steroyl-CoA desaturate (SCD1) inhibitors; fatty acid synthase (FAS) inhibitors; CCK receptor agonists; ghrelin receptor modulators; Pyy 3-36; A dual combination of zonisamide, topiramate/phentermine and pramlintide/metreleptin.

Examples of combination partners for the treatment of atherosclerosis are phospholipase A2 inhibitors; inhibitors of tyrosine-kinases (50 mg to 600 mg), e.g. oxLDL antibodies and vaccines; apoA-1 Milano; ASA; and VCAM-1 inhibitors.
This invention should not be limited in scope by the particular embodiments described herein. Various modifications of the invention in addition to those described herein may become apparent to those skilled in the art from this disclosure. Such modifications are intended to come within the scope of the claims.
All patent applications cited herein are hereby incorporated by reference in their entirety.
Further embodiments, features and advantages of the present invention may become apparent from the following examples. The following examples can be used to illustrate, by way of example and not by way of limitation, the principles of the invention.

<Animal model:>
Sulfonylureas (SU), such as glibenclamide, are one of the most frequently used drugs for diabetes treatment. Long-term treatment with SU results in elevated basal insulin secretion and decreased glucose-stimulated insulin secretion. These properties may play an important role in the development of hypoglycemia and secondary failure of therapy. Db/db mice represent an animal model of type 2 diabetes that exhibits insulin resistance and high levels of plasma glucose. In addition, correlated with animal age, pancreatic β-cells in aging db/db mice fail to ensure high glucose excursions due to enhanced insulin secretion. Therefore, this model is suitable for studying the secondary failure of glibenclamide-induced treatment compared to DPP-4 inhibitors (eg BI 1356).
<Method>
<Animals and containment>
Five week old female db/db mice are obtained from Charles River, Germany. Animals are housed in groups of 5-6 animals under a 12:12 L/D cycle (lights on at 04:00 AM and lights off at 04:00 PM) in a temperature and humidity controlled room. All animals have free access to regular rodent chow (Altromin standard #1324 chow, Denmark) and water ad libitum.
<In vivo experiment>
Compound solutions are administered daily at 08.00 AM on study days 0-59 by oral gavage using a gastric tube connected to a 3 ml syringe (luer-lock ^™ , Becton). Groups of 12 animals are used: vehicle, 0.5% natrosol; BI 1356 3 mg/kg; glibenclamide 3 mg/kg. Body weight, food intake and water intake are recorded daily for the first two weeks and twice weekly for the remainder of the period. Blood glucose and HbA1c levels are measured in the semi-fed state during the 54th day of the experiment and an OGTT (2 g/kg) is performed on the 59th day.
<Monitoring of HbA1c, insulin and blood glucose>
Blood sampling for determination of "fed" blood glucose levels and HbA1c levels is performed at 10.00 AM on Day 54. Prior to their blood sampling, animals are transferred to clean cages without food 2 hours prior to blood sampling. On day 59, OGTT (2 g/kg) is performed after overnight fasting of animals and insulin is detected at t=15 min.
Blood Glucose: For each data point, 10 μl of blood is drawn from the tip of the tail into a microcapillary tube and measured using a Biosen S line glucose analyzer.
Insulin: For each data point, 100 μl of blood is drawn from the tail vein and collected in EDTA tubes. Insulin is measured using a mouse endocrine immunoassay panel (LINCOplex ^™ ) and analyzed using a Luminex100™ system (LincoResearch, Missouri, USA).
HbA1c: is measured using a standard enzymatic assay kit (Bayer) on an automated analyzer.

<Results>
Figures 1 and 2 show HbA1c and glucose levels after 54 days of treatment of 5 week old female db/db mice with the indicated compounds. The DPP-4 inhibitor BI 1356 improves glucose levels as well as HbA1c levels compared to controls. In contrast, the sulfonylurea glibenclamide at a concentration of 3 mg/kg impairs HbA1c values as well as glucose values compared to controls and BI 1356.
Figure 3 shows the increase in insulin during the OGTT test (Oral Glucose Tolerance Test). Only BI 1356 treated animals are able to respond to increased glucose levels with insulin upregulation.
Figure 1 (left bar: vehicle; middle bar: BI 1356; right bar: glibenclamide):
Figure 2 (left bar: vehicle; middle bar: BI 1356; right bar: glibenclamide):
Figure 3 (left bar: vehicle; middle bar: BI 1356; right bar: glibenclamide):

Thus, in animals representing β-cell and secondary failure of SU-induced therapy, the DPP-4 inhibitor BI 1356 is superior to glibenclamide in reducing insulin secretion and HbA1c and glucose.
<Clinical:>
Clinical trials can be used to test the potential use of the DPP-4 inhibitors of the present invention for the purposes of the present invention.
For example, in a randomized, double-blind, placebo-controlled, parallel-group study, the safety and efficacy of a DPP-4 inhibitor of the present invention (e.g., BI 1356 5 mg orally once daily) was evaluated in one or two normal doses. Patients with type 2 diabetes with poor glycemic control (HbA1c 7.0% to 10% or 7.5% to 10% or 11%) despite treatment with antihyperglycemic agents, eg sulfonylureas, are tested.
The sulfonylurea study will examine the efficacy and safety of placebo added to the DPP-4 inhibitors of the present invention versus sulfonylurea background treatment (2-week placebo run-in phase; 18-week double-blind treatment). followed by 1-week follow-up after termination of study medication; background treatment with sulfonylureas administered during the entire study period (including the placebo run-in period at unchanged doses).
Successful treatment is determined by comparing initial and/or placebo group values to determine HbA1c values. A significant change in HbA1c values compared to initial and/or placebo values demonstrates efficacy of the DPP-4 inhibitor for its treatment. Successful treatment is also determined by determining fasting plasma glucose values compared to initial and/or placebo group values. A significant reduction in fasting glucose levels demonstrates efficacy of the treatment. Treatment efficacy is also demonstrated by the development of treatment to target response (ie, HbA1c <7% under treatment).
The safety and tolerability of treatment are examined by analyzing patient status and the occurrence and intensity of relevant changes from baseline, such as adverse events (eg, hypoglycemic episodes, etc.) or weight gain.

Claims (27)

Using one or more conventional oral or parenteral antidiabetic agents selected from metformin, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin or insulin analogues A DPP-4 inhibitor of any of the following formulas (I) to (IV) or a pharmaceutically acceptable agent thereof for the treatment and/or prevention of metabolic diseases in patients with inadequate glycemic control despite treatment salt:
Formula (I)

or formula (II)

or formula (III)

or formula (IV)

[In the formula, R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl , 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4, 6-dimethyl-pyrimidin-2-yl)methyl, and R2 is 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino or (2-( represents S)-amino-propyl)-methylamino]. Treatment of metabolic disorders and/or in patients with inadequate glycemic control despite treatment with one or more oral antidiabetic agents selected from metformin, sulfonylureas, thiazolidinediones, glinides and alpha-glucosidase inhibitors A DPP-4 inhibitor according to claim 1 for prophylaxis. 3. A DPP-4 inhibitor according to claim 1 or 2 for the treatment and/or prevention of metabolic diseases in patients with inadequate glycemic control despite treatment with sulfonylureas. 3. A DPP-4 inhibitor according to claim 1 or 2 for the treatment and/or prophylaxis of metabolic diseases in patients with inadequate glycemic control despite treatment with sulfonylureas alone. 3. A DPP-4 inhibitor according to claim 1 or 2 for the treatment and/or prevention of metabolic disorders in patients with inadequate glycemic control despite combination therapy with a sulfonylurea and metformin. 6. The DPP-4 inhibitor according to any one of claims 1 to 5, which is used for obtaining and/or maintaining glycemic control in type 2 diabetic patients with sulfonylurea secondary failure. 7. A DPP-4 inhibitor according to any one of claims 1 to 6, used in combination with said conventional anti-diabetic drug(s). 8. Any one of claims 1 to 7, used in combination with said sulfonylureas and optionally in combination with one or more other therapeutic agents such as metformin and/or thiazolidinediones (e.g. pioglitazone). DPP-4 inhibitor. Claim 1, wherein said DPP-4 inhibitor is used as a replacement for said sulfonylureas and optionally in combination with one or more other therapeutic agents such as metformin and/or thiazolidinediones (e.g. pioglitazone). 7. The DPP-4 inhibitor according to any one of 6. 10. A DPP-4 inhibitor according to any one of claims 1 to 9, wherein said sulfonylurea is selected from glibenclamide, glipizide and glimepiride. 9. Any of claims 1-8, wherein said DPP-4 inhibitor is used in add-on or initial combination therapy with said sulfonylureas selected from glibenclamide, glipizide and glimepiride with or without metformin. A DPP-4 inhibitor according to claim 1. 12. DPP-4 inhibitor according to any one of claims 1 to 11 for use to improve HbA1c, FPG and/or PPG, reduce glucose excursion and/or improve insulin secretion in said patient agent. 13. The DPP-4 inhibitor according to any one of claims 1 to 12, which is used for the treatment of diabetes such as HbA1c lowering and insulin secretion improvement in patients indicated for first- or second-line sulfonylurea therapy. . 13. The DPP- according to any one of claims 1 to 12 for use in the treatment of diabetes in patients with indications for double sulfonylurea combination therapy such as sulfonylurea + metformin or sulfonylurea + thiazolidinedione or sulfonylurea + insulin. 4 inhibitor. 13. Any of claims 1 to 12 for the treatment of diabetes in patients with indications for triple combination therapy of metformin, sulfonylureas and thiazolidinediones, or metformin, sulfonylureas and insulin, or sulfonylureas, thiazolidinediones and insulin. A DPP-4 inhibitor according to claim 1. 13. A DPP-4 inhibitor according to any one of claims 1 to 12 for use in treating diabetes in patients indicated for insulin therapy. 17. The patient according to any one of claims 1 to 16, wherein said patient suffers from an inappropriate HbA1c value of 7.5-11% or 7.0-10% or 7.5-10% despite treatment with a sulfonylurea. DPP-4 inhibitor. 18. A DPP-4 inhibitor according to any one of claims 1 to 17 for use in preventing or reducing the risk of side effects associated with SU antidiabetic therapy such as hypoglycemia and/or weight gain in said patient. . 19. The DPP-4 inhibitor according to any one of claims 1 to 18, which is used for preventing or delaying progression of diabetes due to SU secondary failure in said patient. 3. The patient is unsuitable for metformin treatment due to intolerance or contraindication to metformin or is in need of reduced dose metformin treatment, e.g., a patient with renal impairment and/or an elderly patient. 20. DPP-4 inhibitor according to any one of 1 to 19. 21. A DPP-4 inhibitor according to any one of claims 1-20 for use in combination with pioglitazone or metformin. The DPP-4 inhibitor according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl) -xanthine,
1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl )-xanthine,
1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[ 4,5-d]pyridazin-4-one,
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino ]-xanthine,
1-[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) -xanthine,
1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino ]-xanthine,
1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) -xanthine,
1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl) -xanthine,
1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidine-1- yl)-xanthine and
1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine. 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl) -xanthine, DPP-4 inhibitor according to any one of claims 1 to 22. A DPP-4 inhibitor for the oral treatment of diabetic patients, characterized in that less than 10%, preferably 7% or less of the administered oral dose is excreted via the kidneys. 25. DPP-4 inhibitor according to claim 24, characterized in that it is excreted unchanged mainly via bile. 26. DPP-4 inhibitor according to claim 24 or 25, characterized in that more than 80%, preferably more than 90% of the administered oral dose is excreted unchanged as the parent drug. 27. DPP-4 inhibitor according to any one of claims 24 to 26, characterized in that its major metabolite is pharmacologically inactive.

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